1. Field of the Invention
This invention relates to a composition and method for treating humans and animals for neoplastic or cancerous growths as well as treating such patients in order to restore or boost hematopoiesis. The composition of the present invention comprises a combination of a cytotoxic T-lymphocyte inducing composition and an agent which is capable of neutralizing or down regulating the activity of tumor secreted immunosuppressive factors.
2. Description of the Related Art
Cytotoxic T-lymphocytes (CTLs) are believed to be the major host mechanism in response to a variety of viral infections and neoplastic or cancerous growth (Greenberg et al., Adv. Immunol., 49:281–355 (1991); Baxevanis et al., Crit. Rev. Oncol.-Hematol., 16:157–79 (1994); Ward et al., Biological Approaches to Cancer Treatment, Biomodulation, pp. 72–97, edited by M. S. Mitchel, New York: McGraw Hill, Inc. (1993)). These cells eliminate infected or transformed cells by recognizing antigen fragments in association with various molecules (termed class I MHC molecules) on the infected or transformed cells (Baxevanis et al., Crit. Rev. Oncol.-Hematol., 16:157–79 (1994); Matsumura et al., Science, 257:927–34 (1992); Long et al., Immunol. Today, 10:232–34 (1989)).
The use of soluble forms of tumor associated antigens (TAA) in subunit vaccines to stimulate tumor specific T-cell immunity is a desirable strategy for developing a safe and effective immunotherapy for cancers. The advantage of using whole protein is that after antigen processing in specialized antigen presenting cells (APC) it contains the entire repertoire of potential peptide epitopes. However, the immunization with whole soluble antigen generally does not activate CTLs. Therefore, to stimulate CTL response to specific protein antigens, various approaches focusing on improving the intracellular antigen delivery to APC have been tried. These include live viral (Moss, B., Science, 252: 1662–67 (1991); Takahashi et al., PNAS USA, 85:3105–09 (1988)) and bacterial (Aldovini et al., Nature (London), 351:479–482 (1991); Sadoff et al., Science, 240:336–38 (1988)) vectors, non-replicating plasmid DNA inoculation (Ulmer et al., Science, 259:1745–49 (1993)), conjugation of protein and peptides to lipophilic compounds (Deres et al., Nature (London), 342:561–64 (1989)) or ISCOM (Takahashi et al., Nature (London), 344:873–75 (1990)). The major concerns for vaccines, based on viral vectors or DNA injections, are safety relating to possible DNA integration into the host cell genome which is particularly relevant to oncogenes with transforming potentials and the induction of anti-vector response in vivo. Furthermore, in immunocompromised individuals, it is safer to use purified antigens in combination with an appropriate non-infectious delivery system with minimal toxicity to induce an immune response.
A safe and advantageous composition by which CTL response may be induced in humans and domesticated or agriculturally important animals and includes the whole soluble protein in a non-infectious delivery system was discovered by Raychaudhuri et al. (U.S. Pat. No. 5,585,103), the contents of which are hereby incorporated by reference in its entirety. The CTL inducing composition involves the use of an antigen formulation which has little or no toxicity to animals, and lacks an immunostimulating peptide (e.g., muramyl dipeptide), the presence of which would decrease the desired response. More specifically, the CTL inducing composition (PROVAX™) comprises the antigen to which the CTL response is desired and a non-toxic antigen formulation which comprises, consists or consists essentially of a stabilizing detergent, a micelle-forming agent, and a biodegradable and biocompatible oil.
However, it has been documented that tumors escape from immune surveillance by secreting factors or cytokines that exert immunosuppressive effects on the functions of both activated and precursor immune cells present locally and systemically. Therefore, cancer patients receiving therapeutic vaccines alone, vaccines which are aimed at enhancing the tumor immunity, may not fully benefit from such vaccine.
Additionally, cancer patients, especially at late stages of the disease, show suppressed hematopoietic activity due to suppression of stem and/or progenitor cells that are vital for the maintenance of healthy bone marrow. This suppression is a result of compounding factors, including radiation and chemotherapy which is used in cancer treatment as well as immunosuppressive factors that may be upregulated by cancer treatments, such as, for example, transforming growth factor-β (TGFβ), a stable family of polypeptide growth factors which are secreted by normal as well as the growing tumors of the host.
Therefore, in view of the aforementioned deficiencies attendant with previously known cancer vaccines and methods of treating tumors, it should be apparent that there still exists a need in the art for more efficient immunotherapeutic treatments and compositions.